{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:41:11Z","timestamp":1787503271323,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,27]],"date-time":"2022-06-27T00:00:00Z","timestamp":1656288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NIGMS R15 GM122016"],"award-info":[{"award-number":["NIGMS R15 GM122016"]}]},{"name":"National Institutes of Health","award":["NCI R01 NC29033"],"award-info":[{"award-number":["NCI R01 NC29033"]}]},{"name":"National Institutes of Health","award":["NCCIH T32 AT010131"],"award-info":[{"award-number":["NCCIH T32 AT010131"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Marine Drugs"],"abstract":"<jats:p>The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPK\u03b1-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPK\u03b1-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.<\/jats:p>","DOI":"10.3390\/md20070418","type":"journal-article","created":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:07:02Z","timestamp":1656374822000},"page":"418","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8807-237X","authenticated-orcid":false,"given":"Daphne","family":"Mattos","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Serrill","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3280-5375","authenticated-orcid":false,"given":"Minh","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Humphreys","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0121-0224","authenticated-orcid":false,"given":"Benoit","family":"Viollet","sequence":"additional","affiliation":[{"name":"CNRS, INSERM, Institut Cochin, Universit\u00e9 Paris Cit\u00e9, F-75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"III","given":"Amos","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Laboratory for Research on the Structure of Matter, and Monell Chemical Senses Center, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2076-1002","authenticated-orcid":false,"given":"Kerry","family":"McPhail","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Ishmael","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6066","DOI":"10.1021\/jo3008622","article-title":"Mandelalides A\u2013D, cytotoxic macrolides from a new Lissoclinum species of South African tunicate","volume":"77","author":"Sikorska","year":"2012","journal-title":"J. Org. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6533","DOI":"10.1002\/anie.201403542","article-title":"Total synthesis and stereochemical reassignment of mandelalide A","volume":"53","author":"Lei","year":"2014","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1021\/acs.orglett.6b00308","article-title":"Discovery of Mandelalide E and Determinants of Cytotoxicity for the Mandelalide Series","volume":"18","author":"Nazari","year":"2016","journal-title":"Org. Lett."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7850","DOI":"10.1021\/acs.jmedchem.7b00990","article-title":"New Mandelalides Expand a Macrolide Series of Mitochondrial Inhibitors","volume":"60","author":"Nazari","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e00096-17","DOI":"10.1128\/mSystems.00096-17","article-title":"Increased Biosynthetic Gene Dosage in a Genome-Reduced Defensive Bacterial Symbiont","volume":"2","author":"Lopera","year":"2017","journal-title":"Msystems"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4217","DOI":"10.1002\/anie.201400605","article-title":"Catalysis-based total synthesis of putative mandelalide A","volume":"53","author":"Willwacher","year":"2014","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1002\/chem.201504230","article-title":"Total Synthesis and Biological Assessment of Mandelalide A","volume":"22","author":"Brutsch","year":"2016","journal-title":"Chemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/jacs.5b12318","article-title":"Enantioselective Total Synthesis of Mandelalide A and Isomandelalide A: Discovery of a Cytotoxic Ring-Expanded Isomer","volume":"138","author":"Veerasamy","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3675","DOI":"10.1021\/jacs.6b01731","article-title":"Total Synthesis of (-)-Mandelalide A Exploiting Anion Relay Chemistry (ARC): Identification of a Type II ARC\/CuCN Cross-Coupling Protocol","volume":"138","author":"Nguyen","year":"2016","journal-title":"J. Am. Chem. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The Metabolism of Tumors in the Body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.124.3215.269","article-title":"On respiratory impairment in cancer cells","volume":"124","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does it Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nature22379","article-title":"Nutrient acquisition strategies of mammalian cells","volume":"546","author":"Palm","year":"2017","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Grasmann, G., Mondal, A., and Leithner, K. (2021). Flexibility and Adaptation of Cancer Cells in a Heterogenous Metabolic Microenvironment. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031476"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.omto.2021.08.015","article-title":"Defueling the cancer: ATP synthase as an emerging target in cancer therapy","volume":"23","author":"Wang","year":"2021","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/ijc.32616","article-title":"Oxidative phosphorylation as a potential therapeutic target for cancer therapy","volume":"146","author":"Sica","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/s41589-021-00897-1","article-title":"A wrench in the motor","volume":"18","author":"Shelton","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"112779","DOI":"10.1016\/j.ejmech.2020.112779","article-title":"Natural products and other inhibitors of F1FO ATP synthase","volume":"207","author":"Patel","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/0003-9861(58)90383-7","article-title":"Antibiotics as tools for metabolic studies. I. A survey of toxic antibiotics in respiratory, phosphorylative and glycolytic systems","volume":"78","author":"Lardy","year":"1958","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"628","DOI":"10.7164\/antibiotics.50.628","article-title":"Apoptolidin, a new apoptosis inducer in transformed cells from Nocardiopsis sp.","volume":"50","author":"Kim","year":"1997","journal-title":"J. Antibiot."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.bcp.2014.11.015","article-title":"Apoptolidins A and C activate AMPK in metabolically sensitive cell types and are mechanistically distinct from oligomycin A","volume":"93","author":"Serrill","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"710","DOI":"10.7164\/antibiotics.54.710","article-title":"Ammocidin, a new apoptosis inducer in Ras-dependent cells from Saccharothrix sp. I. Production, isolation and biological activity","volume":"54","author":"Murakami","year":"2001","journal-title":"J. Antibiot."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/nrm3311","article-title":"AMPK: A nutrient and energy sensor that maintains energy homeostasis","volume":"13","author":"Hardie","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nature06030","article-title":"LKB1 modulates lung cancer differentiation and metastasis","volume":"448","author":"Ji","year":"2007","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1475-4924-2-28","article-title":"Complexes between the LKB1 tumor suppressor, STRAD alpha\/beta and MO25 alpha\/beta are upstream kinases in the AMP-activated protein kinase cascade","volume":"2","author":"Hawley","year":"2003","journal-title":"J. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.semcancer.2019.09.015","article-title":"Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer","volume":"61","author":"Harrison","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41568-019-0226-5","article-title":"Altered cellular metabolism in gliomas\u2014An emerging landscape of actionable co-dependency targets","volume":"20","author":"Bi","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.2337\/db13-0368","article-title":"AMPK: A target for drugs and natural products with effects on both diabetes and cancer","volume":"62","author":"Hardie","year":"2013","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41573-019-0019-2","article-title":"AMP-activated protein kinase: The current landscape for drug development","volume":"18","author":"Steinberg","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101028","DOI":"10.1016\/j.molmet.2020.101028","article-title":"Inducible deletion of skeletal muscle AMPKalpha reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise","volume":"40","author":"Hingst","year":"2020","journal-title":"Mol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.1074\/jbc.RA119.010244","article-title":"Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents","volume":"295","author":"Huet","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.apsb.2015.06.002","article-title":"Regulation of AMP-activated protein kinase by natural and synthetic activator","volume":"6","author":"Hardie","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.molcel.2017.05.032","article-title":"AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance","volume":"66","author":"Garcia","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1016\/j.cub.2003.10.031","article-title":"LKB1 is the upstream kinase in the AMP-activated protein kinase cascade","volume":"13","author":"Woods","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3329","DOI":"10.1073\/pnas.0308061100","article-title":"The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress","volume":"101","author":"Shaw","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/34432","article-title":"A serine\/threonine kinase gene defective in Peutz-Jeghers syndrome","volume":"391","author":"Hemminki","year":"1998","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/ng0198-38","article-title":"Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase","volume":"18","author":"Jenne","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nrc2676","article-title":"The LKB1-AMPK pathway: Metabolism and growth control in tumour suppression","volume":"9","author":"Shackelford","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/s41392-019-0099-9","article-title":"The emerging treatment landscape of targeted therapy in non-small-cell lung cancer","volume":"4","author":"Yuan","year":"2019","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5110","DOI":"10.1158\/1078-0432.CCR-15-0375","article-title":"Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer","volume":"21","author":"Iommelli","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49397","DOI":"10.18632\/oncotarget.10354","article-title":"Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion","volume":"7","author":"Kang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5428364","DOI":"10.1155\/2021\/5428364","article-title":"Enhanced Sensitivity of Nonsmall Cell Lung Cancer with Acquired Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors to Phenformin: The Roles of a Metabolic Shift to Oxidative Phosphorylation and Redox Balance","volume":"2021","author":"Kim","year":"2021","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3892\/or.2022.8266","article-title":"Advances in metforminbased metabolic therapy for nonsmall cell lung cancer (Review)","volume":"47","author":"Chen","year":"2022","journal-title":"Oncol. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.ccr.2012.12.008","article-title":"LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin","volume":"23","author":"Shackelford","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s41589-021-00900-9","article-title":"Apoptolidin family glycomacrolides target leukemia through inhibition of ATP synthase","volume":"18","author":"Reisman","year":"2022","journal-title":"Nat. Chem. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13961","DOI":"10.1073\/pnas.1207912109","article-title":"Oligomycin frames a common drug-binding site in the ATP synthase","volume":"109","author":"Symersky","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.cmet.2010.03.014","article-title":"Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner","volume":"11","author":"Kalender","year":"2010","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"670","DOI":"10.4161\/auto.6.5.12434","article-title":"The combination of metformin and 2 deoxyglucose inhibits autophagy and induces AMPK-dependent apoptosis in prostate cancer cells","volume":"6","author":"Tanti","year":"2010","journal-title":"Autophagy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1158\/0008-5472.CAN-09-2782","article-title":"Targeting cancer cell metabolism: The combination of metformin and 2-deoxyglucose induces p53-dependent apoptosis in prostate cancer cells","volume":"70","author":"Laurent","year":"2010","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1126\/science.1164382","article-title":"An integrated genomic analysis of human glioblastoma multiforme","volume":"321","author":"Parsons","year":"2008","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1056\/NEJMoa0808710","article-title":"IDH1 and IDH2 mutations in gliomas","volume":"360","author":"Yan","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41586-019-0993-x","article-title":"Gboxin is an oxidative phosphorylation inhibitor that targets glioblastoma","volume":"567","author":"Shi","year":"2019","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"109024","DOI":"10.1016\/j.celrep.2021.109024","article-title":"Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth","volume":"35","author":"Sighel","year":"2021","journal-title":"Cell Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1158\/0008-5472.CAN-12-0861","article-title":"AMPK activation by oncogenesis is required to maintain cancer cell proliferation in astrocytic tumors","volume":"73","author":"Rios","year":"2013","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/s41556-018-0126-z","article-title":"AMP kinase promotes glioblastoma bioenergetics and tumour growth","volume":"20","author":"Chhipa","year":"2018","journal-title":"Nat. Cell. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"4287","DOI":"10.1021\/acs.joc.8b00268","article-title":"Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy","volume":"83","author":"Nguyen","year":"2018","journal-title":"J. Org. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"5336","DOI":"10.1128\/MCB.00166-06","article-title":"5\u2032-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments","volume":"26","author":"Laderoute","year":"2006","journal-title":"Mol. Cell Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0065-2571(84)90007-4","article-title":"Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors","volume":"22","author":"Chou","year":"1984","journal-title":"Adv. Enzyme Regul."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1158\/0008-5472.CAN-09-1947","article-title":"Drug combination studies and their synergy quantification using the Chou-Talalay method","volume":"70","author":"Chou","year":"2010","journal-title":"Cancer Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/nrd2487","article-title":"Drug development from marine natural products","volume":"8","author":"Molinski","year":"2009","journal-title":"Nat. Rev. Drug Discov."}],"container-title":["Marine Drugs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/7\/418\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:39:01Z","timestamp":1760139541000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-3397\/20\/7\/418"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,27]]},"references-count":65,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["md20070418"],"URL":"https:\/\/doi.org\/10.3390\/md20070418","relation":{},"ISSN":["1660-3397"],"issn-type":[{"value":"1660-3397","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,27]]}}}